CHAPTER 12 뼈건강개선
Functions of Bone Structural Support Protection Movement Mineral Storage Calcium Phosphate
Skeletal Problems Disease / genetics Osteoporosis (Type I) Multiple myeloma Metastatic bone cancer Rheumatoid arthritis Paget s Disease Hormone ablative therapy Spinal cord or nerve injury Surgery and rehabilitation Aging (Type II Osteoporosis) Bedrest Microgravity
Bone Bone composition 70% mineral (Ca 2+ and PO 4 - as hydroxyapatitie) 22% protein (95% Type I collagen + 5% proteoglycans and other materials) 8% water Two major types of bone Compact (cortical, i.e., long bones) Mechanical and protective functions Cancellous (spongy, i.e., vertebrae) Metabolic regulation of calcium Four types of cells Osteoblasts Osteoclasts Osteocytes Bone lining cells
제 1 절골다공증개선
골다공증 1. 골다공증의정의및개요 뼈로부터칼슘의배출로인해뼈의밀도와강도가약해지게되어골절가능성 이높은상태
골다공증의원인 - 호르몬불균형 - 노화 - 기타위험인자 - 뼈의교체율증가
골밀도의정도 - 세계보건기구에서정한기준에따라같은인종과같은성별의젊은사람의 평균골밀도에서위, 아래표준편차를나타내는 T 값으로표시 - T 값이 -2.5 미만일경우골다골증으로진단
Background The problem Osteoporosis is common Over 50% of women and 30-45% of men over age 50 have osteopenia/osteoporosis White woman over age 50: 50 % lifetime risk of osteoporotic fracture, 25% risk vertebral fracture, 15% risk of hip fracture Man over age 60 has 25% risk osteoporotic fracture 70% over age 80 have osteoporosis
Background Hip fractures are bad 20% patients with hip fracture die within the year 25-30% need placement in skilled nursing facility
What is Osteoporosis? Loss in total mineralized bone Disruption of normal balance of bone breakdown and build up Osteoclasts: bone resorption, stimulated by PTH Calcitonin: inhibits osteoclastic bone resorption Major mechanisms: Slow down of bone build up: osteoporosis seen in older women and men (men after age 70) Accelerated bone breakdown: postmenopausal Normal loss.5% per year after peak in 20s Up to 5% loss/year during first 5 years after menopause
Defining Osteoporosis systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk True Definition: bone with lower density and higher fracture risk WHO: utilizes Bone Mineral Density as definition (T score <-2.5); surrogate marker
Who Gets Osteoporosis? Age Estrogen deficiency Testosterone deficiency Family history/genetics Female sex Low calcium/vitamin D intake Poor exercise Smoking Alcohol Low body weight/anorexia Hyperthyroidism Hyperparathyroidism Prednisone use Liver and renal disease (think about vit d synthesis) Low sun exposure Medications (antiepileptics, heparin) Malignancies (metastatic disease; multiple myeloma can present as osteopenia!) Hemiplegia s/p CVA/ immobility
Diagnosing Osteoporosis Outcome of interest: Fracture Risk! Outcome measured (surrogate): BMD Key: Older women at higher risk of fracture than younger women with SAME BMD! Other factors: risk of falling, bone fragility not all related to BMD Osteoporosis: disease of bone that increases risk of fracture; more than BMD goes into causing a fracture; BMD is important, but in reducing fractures must also consider falls risk, age and other factors!!!
Reducing Fractures 1. Decrease osteoporosis/improve BMD 2. Decrease risk of break: hip protectors 3. Decrease risk of fall
Hip Protectors Padding that fits under clothing Multiple studies demonstrate effectiveness at preventing hip fractures Likely cost effective Problem: adherence!
2. 기능성평가방법 1) 시험관내실험 - 세포를이용하는생체외시험방법을통해평가 - 사람의유사조골세포주를이용하여조골세포의증식능력및분화촉진인자등을살펴봄으로써이루어짐 2) 동물실험 - 흰쥐이용 : 성장과대사속도가빨라골의대사변화를신속하게볼수있음 - 골다공증치료를위한기능성평가가다양함 - Sham operation
Bone Cell Types Osteoblasts Osteoclasts Osteocytes Bone Lining Cells Matrix formation Secretes Type I collagen Regulates mineralization Positioned above osteoid matrix Matrix usually polarized but can surround cells Differentiates to become osteocyte Digests bone Large multinucleated Exhibits ruffled border and clear zone Exhibits polarity with nuclei away from bone surface High density of Golgi stacks, mitochondria and lysozomal vesicles Born from osteoblasts Maintains bone matrix Occupies lucunae Extends filopodia through canaliculi Forms gap junctions with neighboring cells Flat, elongated cells Generally inactive Cover surfaces of inactive bone Thought to be precursor cells to osteoblasts
Haversian System
Cancellous or Trabecular Bone
Why Remodel Bone Allows bone to respond to loads (stresses) Maintain materials properties Allows repair of microdamage Participates in serum Ca 2+ regulation
Remodeling of Bone Resorption accomplished by osteoclasts Form cutting cones to drill holes Haversian system Filled in holes become new osteons Allows bone to respond to physical stress Allows repair of micro damage Participates in plasma calcium control Random remodelling turns over bone Prevent accumulation of brittle material Skeleton is cycled every 4-5 years
Bone Remodeling A Coupled Control System Osteoprogenitor cells Osteoblasts Osteoclasts Mononuclear progenitor cells Osteoblasts have receptors for osteolytic agents Osteoclasts in culture are activated by stimulating osteoblasts Osteoblasts deposit factors in newly formed matrix Osteoclasts produce factors that recruit and activate osteoblasts Factors released as osteoclasts age and die (apoptosis)
Bone Turnover Bone Turnover Relative to Development Formation Resorption Male Female Formation > Resorption High Turnover Formation = Resorption Formation < Resorption Formation < Resorption Low Turnover
Bone Strength Determinants of strength Geometry Bone mineral density Materials properties Bone growth Growth needed during development Growth also needed to withstand increased loads
Support of Osteocyte-based Mechanism Osteocyte network Large surface area in contact with bone 2 orders of magnitude more than any other cell type Provides intracellular and extracellular route of communication Isolated turkey ulna stimulated with loading causes significant activation of osteocytes 1 Hz at 500-2,000 (10-6 ) strain ( l/l) Osteocytes do not appear to respond to static loads Intermittent stresses cause significant changes in osteocytes which suggest function as mechanosensors
Osteocyte Candidate Signaling Molecules Nitric Oxide Small molecule, diffuses quickly Produced rapidly Stimulates production of IGF via both autocrine and paracrine mechanisms Sclerostin Protein produced only by osteocytes Powerful inhibitor of osteoblasts In new bone (Haversian), osteocytes closer to center of channel produce most sclerostin
Summary of Bone Feedback Control System Hormones / Cytokines External Loads Bone mechanical properties Osteoclasts - Osteoblasts Hormones / Cytokines + Strain (Deformation) - Canaliculi network resistance Osteocytes produce Nitrous oxide / Prostaglandins Osteocytes produce sclerostin Streamin g flows and osteocyte s deforme d SGPs or direct strain
Stress Shielding Occurs with artificial implants Stiffness of implant much greater than natural bone Does not transmit stress uniformly and fully into native bone at interface Bone becomes resorbed at interface and implant becomes loose
Effects of Exercise on Bone Two types of studies conducted Compare trained athletes with sedentary people Athletes and chronic exercisers have higher BMD Competitive runners in 60s have ~40% greater BMD than controls Weight lifters have 10-35% greater spine BMD Tennis players have 30% greater thickness of dominant humerous Correlate level of fitness with BMD (Effect not obvious) Early life experience is important (Peak BMD) Women who get hip fractures have lower levels of occupational or leisure activity from 15-45 years old Significant associations between hip BMD and early-life exercise both men and women
Bone density (%) Skeletal Response to Exercise 30 Sedentary Moderately Active 0 Normal Range Lazy zone -40 Spinal injury, immobolization, bed rest, space flight. Changes only occur with significant habitual changes in activities over several months
Mechanisms of Exercise Effects Increased habitual strain causes an increase in net bone formation Returns bone strain to normal control setpoint Studies with intact bone Mechanical loading causes: Formation on periosteal surface without initial resorption Periosteal cell proliferation
Interaction of Age with Exercise Increasing age causes deficits in response (I.e., gain of system goes down) Probably caused by multiple factors Women from 60-80 show BMD increase of only 5-8% with exercise Increases in BMD with exercise reverts to normal within a few months of terminating training Exercise clearly helps maintain bone as system gain or setpoint is reduced
Osteoporosis Defined as reduction in bone mass and micro-architecture that leads to susceptibility to fracture Normal Osteoporotic
Costs of Osteoporosis 10,000,000 cases in U.S. alone Affects 1 in 2 women and 1 in 8 men > 50 years old Causes 1.5 million fractures/year - 700,000 spine, 300,000 hip and 300,000 wrist, 25,000 deaths from complications Menopause is the biggest risk factor for disease Disease often not diagnosed until after 1 or more fractures have occurred Prevalence could rise to 41 million by 2015 from 28 million today Cost to health care estimated at $14 billion ($38M/day) Psychological and social effects of disease are immense
Development of Osteoporosis Formation takes 3-4 months to replace bone resorbed in 2-3 weeks Osteoclast recruitment is increased Osteoblast-osteoclast Coupling is interrupted Factors recruiting osteoclasts may not adequately recruit osteoblasts Lack of estrogen may lead to less IGF-1 incorporated into new bone reduces later osteoblast recruitment Gain or setpoint in mechanosensory feedback loop may be reduced
Issue of Peak Bone Mass Bone mass peaks in the 20 s, starts dropping in the late 30 s and accelerates significantly after menopause Risk for osteoporosis depends on peak mass and rate of loss Peak bone mass depends on Genetics Calcium, diet, exercise, etc. in youth
Bone Remodeling A Coupled Control System
Osteoprotegerin (OPG) Seminal paper published in 1997 Osteoprotegerin: A novel secreted protein involved in the regulation of bone density, Simonet et al, Cell, 234:137-142 OPG member of TNF receptor superfamily soluble receptor Shown to affect bone density Lack of OPG Normal OPG Extra OPG
OPG / RANKL / RANK Receptor RANKL and OPG are secreted by osteoblasts and bone marrow stromal cells RANKL functions to promote osteoclast formation and activation and inhibit apoptosis Hormones Cytokines Osteoblasts Bone RANK RANK Ligand OPG RANK Osteoclast Osteoclast Precursor OPG functions as a decoy receptor to prevent RANKL signaling; ratio of RANKL to OPG dictates bone mass and structural properties Current extensive research is elucidating the role of OPG and RANKL in a wide variety of bone-related diseases
Figure. Schematic representation of the pathways regulating osteoclast differentiation.
Denosumab (OPG mimetic) Fully human monoclonal antibody to RANK Ligand IgG 2 High affinity for RANK Ligand (K d 3 x 10 12 M) Does not bind to TNFα, TNFß, TRAIL, or CD40L Monoclonal Antibody Model Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ, et al. Nature. 2003;423:337-342.
Mechanism of Action for Denosumab Osteoclast Activation Denosumab OPG RANKL RANK Osteoclast Formation, Function and Survival Inhibited CFU-M Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Mature Osteoclast Bone Adapted from Boyle WJ, et al. Nature. 2003;423:337-42.
3) 임상시험 - 정상군의경우폐경하지않은여성을시험대상으로선정 - 시험군의경우약물, 또는에스트로겐을복용하지않은폐경여성혹은난소절제여성으로선정 - 기본조사 : 연령, 신장, 체중, 체질량지수, 폐경기간, 폐경시작나이및출산횟수 - 생화학적검사 : 골형성및골흡수지표관찰 - 조직학적검사 : 골밀도, 방사선관찰
3) 임상시험 (1) 골형성지표분석 1Bone alkaline phosphatase(balp) - 혈정에소맥배아응집소를용해하고렉틴용액을첨가한뒤희석된트리톤 -X 100 용액을 첨가하여원심분리하여상층액에있는 ALP 수치를측정하는것 2 오스테오칼신 (Osteocalcin) - 혈중오스테오칼신은 osteocalcin myria 키트를이용하여방사면역분석시험법에따라 측정 3 콜라겐프로펩타이드유형 Ⅰ - 효소면역검사법 (ELISA) 키트로측정
(2) 골흡수지표분석 1 콜라겐텔로펩타이드유형 Ⅰ - 뇨중콜라겐텔로펩타이드유형을효소면역검사법키트로측정 2 피리디놀린 (pyridinoline) - 뇨중피리디놀린의측정을콜라겐교차결합키트를이용해효소면역검사법으로측정 3 데옥시피리디놀린 (deoxypyridinolin) - 노중데옥시피리디놀린의측정은원심분리하여뇨량을잰다음 pyrilinks-d 키트를사용 하여효소면역검사법에의해분석
(3) 칼슘대사 - 혈청중칼슘함량은회화시킨후 AAS 로측정한다. - 칼슘생체이용률은방사성동위원소 (radio-isotype) 를이용하여분석 (4) 호르몬 1부갑상선호르몬 (parathyroid hormone) - DSL-8000 ACTIVE TM Intact PTH IRMA 키트를이용하여비경쟁적방사면역분석시험을수행 2 혈중칼시토닌 (calcitonin) - DSL-7500 ACTIVE TM Calcitonine IRMA 키르를이용하여비경쟁적방사면역분석시험 을수행 3 에스트로겐 (estrogen) - 혈청중에스트라디올 (estradiol) 함량은 estradiol RIA 키트를이용하여방사면역분석시 험에따라측정
(5) 골밀도, 골무기질함량및총골칼슘측정 - 시험후척추및골반, 오른쪽대퇴골등과총골칼슘량을이중에너지 X- 선흡수계측법을 이용하여척추및골반등과같은체중이실리는부위와전신골밀도를측정
hormone
3. 골다공증개선건강기능식품및효능 1) 고시형건강기능식품 (1) 칼슘 - 우유및유제품, 채소및과일, 뼈째먹는생선, 두류등에다량함유 - 최근, 칼슘강화주스, 칼슘고형두부등과같은강화식품이개발되는추세 - 칼슘은뼈와치아를형성하는데필요하다. - 칼슘은신경과근육의기능을유지하는데필요하다. - 칼슘은정상적인혈액응고에필요하다.
(2) 비타민 D - 비타민 D는종류가최소 10가지이상으로, 대표적인것으로는비타민 D2 (ergo-calciferol) 와비타민 D3 (cholecalciferol) 가생리적으로중요한기능을함 - 비타민 D는칼슘과인이흡수되고이용되는데필요하다. - 비타민 D는뼈를형성하고유지하는데필요하다.
Fracture Reduction Goal: prevent fracture, not just treat BMD Osteoporosis treatment options Calcium and vitamin D Calcitonin Bisphosphonates Estrogen replacement Selective Estrogen Receptor Modulators Parathyroid Hormone
Osteoporosis Treatment: Calcium and Vitamin D Fewer than half adults take recommended amounts Higher risk: malabsorption, renal disease, liver disease Calcium and vit D supplementation shown to decrease risk of hip fracture in older adults 1000 mg/day standard; 1500 mg/day in postmenopausal women/osteoporosis Vitamin D (25 and 1,25): 400 IU day at least; Frail older patients with limited sun exposure may need up to 800 IU/day
Osteoporosis Treatment: Calcitonin Likely not as effective as bisphosphonates 200 IU nasally/day (alternating nares) Decrease pain with acute vertebral compression fracture
Osteoporosis Treatment: Bisphosphonates Decrease bone resorption Multiple studies demonstrate decrease in hip and vertebral fractures Alendronate, risodronate IV: pamidronate, zolendronate (usually used for hypercalcemia of malignancy, malignancy related fractures, and multiple myeloma related osteopenia) Ibandronate (boniva): once/month Those at highest risk of fracture (pre-existing vertebral fractures) had greatest benefit with treatment
Bisphosphonates: Contraindications Renal failure Esophageal erosions GERD, benign strictures, most benign GI problems are NOT a contraindication Concern for esophageal irritation/erosions from direct irritation, recommendations to drink water after and not lie down at least 30 minutes Reality: no increased GI side effects compared to placebo group in multiple studies
Osteoporosis Treatment: Selective Estrogen Receptor Modulators Raloxifene FDA recommended Decrease bone resorption like estrogen No increased risk cancer (decrease risk breast cancer) Increase in vasomotor symptoms associated with menopause
Osteoporosis Treatment: PTH Teriparatide Why PTH when well known association with hyperparathyroidism and osteoporosis??? INTERMITTENT PTH: overall improvement in bone density Optimal bone strength relies upon balance between bone breakdown and bone build up; studies with increased density but increased fracture risk/fragility with flouride show that just building up bone is not enough!!!
Intermittent PTH: Teriparatide Studies suggest improved BMD and decreased fractures?risk osteosarcoma with prolonged use (over 2 years): studies with rats SQ, expensive Option for severe osteoporosis, those on bisphophonates for 7-10 years, those who can not tolerate oral bisphosphonate Optimal effect requires bone uptake Not for use in combination with Bisphosphonate! May need to stop bisphosphonate up to 1 year prior
(3) 글루코사민 - 아미노산과당이결합한형태인아미노당의일종으로관절의연골을구성하는성분 - 새우나게와같은갑각류의껍질에존재하는키틴성분으로부터추출 - 관절및연골건강 의기능성이인정됨 (4) N- 아세틸글루코사민 - 새우나게와같은갑각류의껍질에존재하는키틴을효소분해하여생산 - 관절및연골건강 의기능성이인정됨 (5) 뮤코다당 단백 - 동물점액성다당류의일종으로뮤코다당체, 뮤코다당질의약칭 - 소, 돼지, 양, 사슴, 상어, 가금류, 오징어, 게, 어패류의연골조직을열수추출및효소분해하여여과, 농축, 건조등의공정을거쳐식용에적합하도록정제하고건조한것 - 관절및연골건강 의기능성이인정됨
(6) 프락토올리고당 - 과일및채소와버섯등에존재 - 설탕에과당을전이시키거나, 이눌린을이눌레이스로부분가수분해하여생성됨 - 칼슘흡수에도움 의기능성이인정됨 (7) 대두이소플라본추출물 - 발효된대두배아를주정추출하여생성 - 다이드제인과제니스테인이지표성분으로서, 둘의총합이 30~40% 가되게함 - 뼈건강에도움을줄수있습니다 - 기타기능Ⅱ로기능성이인정됨
Estrogens decrease osteoclast formation by down-regulating RANKLinduced activation of JNK and subsequent phosphorylation (and activation) the Jun transcription factor. This occurs within 5 minutes of estrogen treatment in vitro and is reversed by treatment with estrogen antagonist.
2) 개별인정형건강기능식품 (1) 차조기등복합추출물 (KD-28) - 갈근, 인진및차조기세가지재료를주정을이용하여추출 - 푸에라린, 스코폴레틴, 아피제닌이각각원료의지표성분임 - 관절건강에도움을줄수있습니다 - 기타기능Ⅱ 로기능성이인정됨 (2) 로즈힙분말 - 건조시킨로즈힙열매로만든다. - 하이페로사이드가지표성분으로알려져있다. - 관절및연골건강에도움을줄수있습니다 기타기능Ⅱ로기능성이인정됨 (3) 황금등복합물 - 황금물추출분말 (80%), 아선약물추출분말 (20%) 을합하여만듦 - 바이탈린과카테킨이지표성분으로각각 18%, 3% 가되도록함 - 관절건강에도움이될수있습니다 - 기타기능Ⅱ 로기능성이인정됨
(4) 초록입홍합추출오일복합물 - 초록입홍합초임계추출물, 올리브오일, D-a-토코페롤세가지원료를혼합하여만듦 - EPA, DHA, a-리놀렌산등의오메가-3-불포화지방산혼합물이지표성분으로, 25% 이상이되도록함 - 관절건강에도움이될수있습니다 - 기타기능Ⅱ 로기능성이인정됨 (5) 기타 - 칼슘-PGA: 체내칼슘흡수촉진에도움을줄수있다 로기능성을인정받음 - 호프추출물 : 관절건강에도움을줄수있다 로기능성을인정받음 - 지방산복합물 : 관절건강에도움을줄수있다 로기능성을인정받음
reference Funtional food 이형주외수학사 handouts